Interaction of DNA Methyltransferase Dnmt3a with Phosphorus Analogs of S-Adenosylmethionine and S-Adenosylhomocysteine

• Published in: Molecular biology (New York) Vol. 57; no. 4; pp. 747 - 754
• Main Authors: Filonov, V. L., Khomutov, M. A., Sergeev, A. V., Khandazhinskaya, A. L., Kochetkov, S. N., Gromova, E. S., Khomutov, A. R.
• Format: Journal Article
• Language: English
• Published: Moscow Pleiades Publishing 01-08-2023; Springer Nature B.V
• Subjects: Adenosylmethionine; Biochemistry; Biomedical and Life Sciences; CpG islands; Cytosine; DNA methylation; DNA methyltransferase; Epigenetics; Gene expression; Homocysteine; Human Genetics; L-Homocysteine; Life Sciences; Methionine; Nucleotide sequence; Phosphorus; S-Adenosylmethionine; Structural-Functional Analysis of Biopolymers and Their Complexes; homocysteine; inhibitors; methionine; DNA methylation; substrates; organophosphorous analogs; adenosyl
• ISSN: 0026-8933; 1608-3245
• DOI: 10.1134/S0026893323040064

Enzymatic methyltransferase reactions are of crucial importance for cell metabolism.
S
-Adenosyl-
L
-methionine (AdoMet) is a main donor of the methyl group. DNA, RNA, proteins, and low-molecular-weight compounds are substrates of methyltransferases. In mammals, DNA methyltransferase Dnmt3a de novo methylates the C5 position of cytosine residues in CpG sequences in DNA. The methylation pattern is one of the factors that determine the epigenetic regulation of gene expression. Here, interactions with the catalytic domain of Dnmt3a was for the first time studied for phosphonous and phosphonic analogs of AdoMet and
S
-adenosyl-
L
-homocysteine (AdoHcy), in which the carboxyl group was substituted for respective phosphorus-containing group. These AdoMet analogs were shown to be substrates of Dnmt3a, and the methylation efficiency was only halved as compared with that of natural AdoMet. Both phosphorus-containing analogs of AdoHcy, which is a natural methyltransferase inhibitor, showed similar inhibitory activities toward Dnmt3a and were approximately four times less active than AdoHcy. The finding that the phosphonous and phosphonic analogs are similar in activity was quite unexpected because the geometry and charge of their phosphorus-containing groups differ substantially. The phosphorus-containing analogs of AdoMet and AdoHcy are discussed as promising tools for investigation of methyltransferases.